Vascular risk factors and vascular disease are increasingly recognized as major contributors to cognitive impairment and dementia, including Alzheimer's disease (AD), but tend to be understudied despite their potential role as a target for prevention. As a stroke neurologist, with doctoral training in Clinical Investigation, the PI proposes to evaluate a particular form of vascular disease-congestive heart failure (CHF)-in association with cognitive performance and ?-amyloid deposition, which by leading hypotheses is the cause of AD. In one already-collected community-based cohort (The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), funded through NHLBI and NINDS with Dr. Gottesman as a coinvestigator) and its ancillary R01 sub-cohort (The ARIC-PET study, funded through an NIA R01 with Dr. Gottesman as PI), Dr. Gottesman will evaluate associations between subclinical cardiac dysfunction and cognitive decline and ?- amyloid deposition, each. In addition, in an ongoing prospective clinical heart failure cohort (Diuresis Clinic Cognitive Cohort), Dr. Gottesman will evaluate the features of CHF that are associated with cognitive impairment, will evaluate if cognitive deficits are reversible in the setting of treatment of decompensated CHF, and will explore mechanism for any transient cognitive deficits in this setting (particularly, changes in cerebral blood flow and in inflammation). These studies will provide the structure for the PI's proposed mentoring plan, as will her other ongoing research in the area of the vascular contribution to cognitive impairment and AD, with an emphasis on neuroepidemiologic approaches. As part of this mid-career mentoring award, the PI will focus on training future investigators interested in the vascular contribution to AD. Because this is an area in which interventions or preventive therapies might be undertaken that could either directly reduce AD burden, or could identify persons at high risk who might benefit from future AD-specific treatments, it is clear that trainees are needed who understand the importance of how to measure and define vascular risk factors and disease, and how to address potential biases in analyses related to persons with cognitive impairment and dementia. The mentoring plan will focus on direct exposure to primary data collection within clinical cohorts and within epidemiologic cohorts, secondary data analysis of epidemiologic data, and an interdisciplinary approach to research. The proposed research in this K-24 application uses a particular vascular disease model (CHF) that is a likely important contributor to cognitive impairment and dementia, and in which impairments might be reversible or preventable. The specific goals of this K-24 application are: (1) to characterize and explore mechanisms for cognitive dysfunction associated with congestive heart failure; and (2) to recruit and mentor new investigators in a range of disciplines from the Schools of Medicine and Public Health at Johns Hopkins, to include, but not limited to, neurology, psychiatry, neuropsychology, geriatrics, epidemiology, and biostatistics.